Synthesis Of Methotrexate Research Articles

Optimization of N‐alkylation in the Synthesis of Methotrexate and Pteridine‐based Derivatives Under Microwave‐Irradiation

AbstractMethotrexate (MTX) and its pteridine‐based derivatives represent an attractive chemotype for the development of bioactive molecules. However, the synthesis of pteridines suffers from several drawbacks. Here we describe a new efficient and improved microwave‐assisted lab‐scale process for the preparation of MTX and congeners. Starting from the commercially available 2,4‐diamino‐6‐(hydroxymethyl)pteridine (Pt‐OH), MTX was obtained with an overall 94% yield through a three steps procedure. The crucial yield‐limiting and time‐consuming step of SN2 substitution between halogenated pteridine and nucleophilic aromatic amine was taken. The innovative process, conducted under microwave irradiation, improved yield and purity, and in particular reduced the reaction time from days to 20 minutes. The optimized protocol was successfully applied to the synthesis of diverse pteridine‐based derivatives and to the preparation in gram‐scale of antiparasitic MTX derivatives for in vivo studies. This new optimized synthetic procedure therefore represents a worthy alternative to the current protocols for the preparation of pteridine‐based derivatives.

Synthesis of methotrexate (Mtx) drug attached, water dispersible superparamagnetic Fe3O4 nanoparticles and a time dependent study of release of the drug under biological conditions

Synthesis of methotrexate (Mtx) drug attached, water dispersible superparamagnetic Fe3O4 nanoparticles and a time dependent study of release of the drug under biological conditions

Synthesis of methotrexate ?,?-bis(amides) and correlation of thermotropic and DPPC biomembrane interaction parameters with their anticancer activity

The interaction of MTX and some aliphatic his(amide) derivatives with synthetic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) biomembranes was investigated. The drug-membrane model interaction was carried out by differential scanning calorimetry. Anticancer activity of MIX his(amides) was evaluated on cultures of a human leukemic cell line (CCRF-CEM) in comparison with MTX. Compounds were tested at a concentration ranging between 10 nM and 1 μM. The MTX is able to interact with the outer part of the phospholipid bilayers due to its polar nature. Results showed that the amide derivatives of MTX, presenting a marked lipophilic character, are able to interact with the hydrophobic core of the DPPC bilayers, thus perturbing the packing order of the phospholipid bilayers. Particularly, a reduction of the enthalpy values linked to the transition from the gel state to the liquid crystal state of DPPC membranes was observed. This effect is a function of the type and molar fraction of the various compounds. The in vitro antitumor activity on leukemic CCRF-CEM cells was higher for MTX-bis(tetradecylamide) than for the other derivatives. The biological effectiveness of the various MTX derivatives correlates very well with the enthalpy of the transition of drug-loaded DPPC biomembranes.

The effect of the rate of cell proliferation on the synthesis of methotrexate poly-γ-glutamates in two human breast cancer cell lines

The synthesis of methotrexate poly-γ-glutamates by the MDA-MB-436 and MCF-7 human breast cancer cell lines is highly dependent on the rate of cell growth. Slowly proliferating cells accumulate methotrexate to the same extent as rapidly proliferating cells but convert a lower percentage of the drug to polyglutamate forms. The longest polyglutamate-derivatives of methotrexate are generally only synthesized when the cells are doubling rapidly. The MDA-MB-436 cells exhibit a biphasic response of doubling time and polyglutamation to increasing initial cell number. Extremes of cell density are associated with long doubling times and reduced polyglutamate synthesis. MCF-7 cells show increasing doubling time and decreasing polyglutamate synthesis in response to increasing initial cell number.

The effect of leucovorin on the synthesis of methotrexate poly-γ-glutamates in the MCF-7 human breast cancer cell line

The modulating effects of leucovorin on the synthesis of methotrexate (MTX) polyglutamates in the MCF-7 human breast cancer cell line have been investigated using a paired-ion high performance liquid chromatography (HPLC) system. Leucovorin decreased the intracellular level of MTX and profoundly affected polyglutamate synthesis irrespective of whether it was administered with or after MTX. Inhibition of MTX polyglutamate synthesis was also observed when concentrations of leucovorin too low to affect intracellular levels of MTX were employed. Leucovorin did not promote efflux of MTX from the MCF-7 cells and did not affect the distribution of the retained drug amongst the various polyglutamate forms.